This application is a 371 of PCT/JP99/00412 Feb. 1, 1999.
1. Field of the Invention
The present invention relates to a novel trimethylcyclohexane derivative and a melanin production inhibitor and/or a fragrance fixative comprising this trimethylcyclohexane derivative as a main component, as well as a dermal formulation comprising these melanin production inhibitor and/or a fragrance fixative.
2. Description of the Related Art
An irradiation of a ray such as UV light to skin causes a sunburn and a change in the color of the skin tissue into black as a result of the production and the deposition of melanin in a chromatophore which is triggered by a irritative effect of the exposure to the UV or a hormone and the like. Freckles and liver spots reflect the fixative and the deposition of melanin throughout the entire layer of a local epidermis.
Such melanin synthesis in a epidermis is believed to be attributable to melanin production as a result of an oxidative polymerization of a tyrosine catalyzed by a tyrosinase which is an oxidase biosynthesized in a chromatophore.
An inhibition of the process of such melanin production and deposition is an aim of the development of a whitening agent and has been a subject in various studies.
The effect of vitamin C, cysteine, kojic acid, arbutin, glutathione, hydroquinone or an extract from a naturally occurring material as a substance capable of inhibiting tyrosinase activity and thus suppressing melanin production and as a substance capable of decoloring and whitening melanin once produced has already been established. Nevertheless, none of these substances is satisfactory in terms of stability, safety and odor, and has a sufficient whitening effect, and no satisfactory whitening agent has been obtained.
Other compounds having melanin production inhibiting effects which have been reported are tetrahydroionol and derivatives thereof (JP-A-8-73334, JP-A-8-73335, JP-A-8-73336 and JP-A-8-73359) and xcex2-ionone and a dihydro form thereof (JP-A-8-198747). However, the melanin production inhibiting effect of any of these compounds is not satisfactory. In addition, their relatively intense odors pose a requirement of an effort to reduce the adverse effect on the fragrance of a final product.
Also known are the trimethylcyclohexane derivatives represented by Formula (3) and Formula (4): 
wherein A represents Cxe2x95x90O or CHxe2x80x94OH, R4represents ethyl, n-propyl and isobutyl, and, 
wherein R5 represents ethyl, n-propyl, n-butyl and isobutyl.
A compound of Formula (3) is described only as an intermediate or a by-product in synthesizing a fragrance compound, 1-alkyl-substituted-3-(2xe2x80x2,2xe2x80x2,6xe2x80x2-trimethylcyclohexan-1-yl)propan-1-ol (JP-B-3-80780, JP-A-4-226930), while a compound of Formula (4) is described only as a fragrance (JP-A-4-21642, JP-B-7-25709). Since any of the compounds described is an intensely fragrant substance, it can not be used as a fragrance fixative. None of the publications described above contain an inhibitory effect on melanin production by a viable chromatophore.
On the other hand, a conventional method for formulating fragrant substances to prepare an excellent fragrance composition involves an incorporation of various fixatives which adjust the aroma profile and the fixative of a fragrant substance into a fragrance for the purpose of sustaining an intended fragrance.
Those employed typically are dipropylene glycol, triethyl citrate, benzyl benzoate and the like, but these fixatives do not have satisfactory fixative effects.
An objective of the invention is to provide a novel trimethylcyclohexane derivative useful as a melanin production inhibitor or as a fragrance fixative. Another object of the invention is to provide a melanin production inhibitor and/or a fragrance fixative comprising this trimethylcyclohexane derivative as a main component. Still another object of the invention is to provide a dermal formulation comprising such melanin production inhibitor and/or fragrance fixative.
The inventors made an effort to solve the problems encountered currently as discussed above and finally discovered that a novel trimethylcyclohexane derivative represented by Formula (1): 
wherein A represents Cxe2x95x90O or CHxe2x80x94OH, n represents 2, R1 represents hydrogen or a methyl group, R2 represents a straight or branched, saturated or unsaturated hydrocarbon group having 3 to 10 carbon atoms, and a dotted line represents a saturated or unsaturated carbon-carbon bond, can solve the problems, thus establishing the invention.
Thus, the inventors discovered that Compound (1) represented by Formula (1) shown above has a potent inhibitory effect on melanin production by a viable chromatophore, that a melanin production inhibitor consisting of Compound (1) is excellent in terms of stability and safety and can exhibit an extremely higher melanin production inhibiting effect when compared with a conventional product, that Compound (1) has an ability of sustaining the fragrant component of a fragrance for a prolonged period and that a fragrance fixative consisting of Compound (1) can promote the intended aroma characteristics and the fragrance fixative markedly.
In addition, it was also discovered that Compound (1) which is odorless itself does not exert any influence on the smell of a dermal formulation containing it and is stable and safe in a formulation or a base, and has an excellent melanin production inhibiting effect and an excellent fragrance fixative effect.
A novel trimethylcyclohexane derivative (1) represented by the above Formula (1), a melanin production inhibitor and/or a fragrance fixative comprising this compound, and a dermal formulation comprising such melanin production inhibitor and/or a fragrance fixative are described below.
(1) A trimethylcyclohexane derivative represented by Formula (1): 
wherein A represents Cxe2x95x90O or CHxe2x80x94OH, n represents 2, R1 represents hydrogen or a methyl group, R2 represents a straight or branched, saturated or unsaturated hydrocarbon group having 3 to 10 carbon atoms, and a dotted line represents a saturated or unsaturated carbon-carbon bond.
(2) A trimethylcyclohexane derivative wherein R2 in Formula (1) according to Section (1) described above is selected from the group consisting of n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, isopropyl, isobutyl, sec-butyl, tert-butyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-l-propenyl, 2-methyl-2-propenyl, 1-ethyl-1-ethenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, 2,6-dimethylheptyl, 2,6-dimethyl-1-heptenyl, 2,6-dimethyl-5-heptenyl and 2,6-dimethyl-1,5-heptadienyl groups.
(3) A trimethylcyclohexane derivative wherein R2 in Formula (1) according to Section (1) described above is selected from the group consisting of n-propyl, n-butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-ethyl-1-ethenyl, 1-methyl-1-propenyl and 1-methyl-2-propenyl groups.
(4) A melanin production inhibitor comprising one or more of trimethylcyclohexane derivatives according to Sections (1) to (3) described above.
(5) A fragrance fixative comprising one or more of trimethylcyclohexane derivatives according to Sections (1) to (3) described above.
(6) A dermal formulation comprising one or more melanin production inhibitors and/or fragrance fixatives according to Sections (4) to (5) described above.
(7) A melanin production inhibitor comprising one or more trimethylcyclohexane derivatives represented by Formula (2): 
wherein A represents Cxe2x95x90O or CHxe2x80x94OH, n represents 0, R1 represents hydrogen or a methyl group, R3 represents a straight or branched, saturated or unsaturated hydrocarbon group having 2 to 4 carbon atoms, and a dotted line represents a saturated or unsaturated carbon-carbon bond.
(8) A dermal formulation comprising one or more melanin production inhibitors according to Section (7) described above.
The present invention is described in further detail below.
R2 in Compound (1) of the invention may be, for example selected from, but is not limited to, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, 4-methylpentyl, 5-methylhexyl, 6-methylheptyl, 7-methyloctyl, 8-methylnonyl, 1-methylbutyl, 1-methylpentyl, 1-methylhexyl, 1-methylheptyl, 1-methyloctyl, 1-methylnonyl, 2,6-dimethylheptyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 6-heptenyl, 7-octenyl, 8-nonenyl, 9-decenyl, 1-pentenyl, 1-hexenyl, 1-heptenyl, 1-octenyl, 1-nonenyl, 1-decenyl, isopropenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-ethyl-1-ethenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, 3-methyl-2-butenyl, 4-methyl-3-pentenyl, 5-methyl-4-hexenyl, 6-methyl-5-heptenyl, 7-methyl-6-octenyl, 8-methyl-7-nonenyl, 2,6-dimethyl-5-heptenyl, 2,6-dimethyl-1-heptenyl, 2,6-dimethyl-1,5-heptadienyl groups and the like.
Preferably, R2 is n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, isopropyl, isobutyl, sec-butyl, tert-butyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-ethyl-1-ethenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, 2,6-dimethylheptyl, 2,6-dimethyl-1-heptenyl, 2,6-dimethyl-5-heptenyl and 2,6-dimethyl-1,5-heptadienyl groups.
Those exemplified more preferably are hydrocarbon groups each having 3 to 4 carbon atoms with which the melanin production inhibiting effect becomes especially high, such as n-propyl, n-butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-ethyl-1-ethenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl groups and the like.
Most preferably, R2 is selected from n-propyl, n-butyl, isobutyl, se-butyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl and 2-methyl-1-propenyl groups.
R3 in Compound (2) employed as a melanin production inhibitor according to the invention may be, for example selected from, but is not limited to, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, allyl groups and the like.
Preferred examples of a compound employed as a melanin production inhibitor and/or a fragrance fixative according to the invention are, but are not limited to, the following compounds.
Compound (1) of the invention can be classified into one of the 4 types represented by the following structures (1)-1, (1)-2, (1)-3 
and (1)-4.
In addition to Compound (1) of the invention described above, preferred examples of Compound (2) used as an inventive melanin production inhibitor are, but are not limited to, the following compounds.
Similar to Compound (1), Compound (2) can also be classified into one of 4 types represented by the following structures (2)-1, (2)-2, (2)-3 and (2)-4. 
Compounds (1)-1, (1)-2, (1)-3 and (1)-4 represented by Formula (1) according to the invention can be, for example, synthesized as illustrated in the following schemes.
In the following schemes, R1 represents hydrogen or a methyl group and R2 represents a straight or branched, saturated or unsaturated hydrocarbon group having 3 to 10 carbon atoms. 
Thus, 2,2,6-trimethylcyclohexane carbaldehyde (5) and a corresponding ketone (R1xe2x80x94CH2xe2x80x94COxe2x80x94CH2xe2x80x94CH2xe2x80x94R2) are subjected to an aldol condensation under a known condition to obtain a 1-(2xe2x80x2,2xe2x80x2,6xe2x80x2-trimethylcyclohexan-1xe2x80x2-yl)pentan-1-en-3-one derivative represented by Formula (1)-1, which is subjected to a reduction using a known reducing agent to obtain a 1-(2xe2x80x2,2xe2x80x2,6xe2x80x2-trimethylcyclohexan-1xe2x80x2-yl)pentan-1-en-3-ol derivative represented by Formula (1)-2, which is then subjected to a hydrogenation using a known hydrogenation catalyst to obtain a 1-(2xe2x80x2,2xe2x80x2,6xe2x80x2-trimethylcyclohexan-1xe2x80x2-yl)pentan-3-ol derivative represented by Formula (1)-4. Alternatively, a 1-(2xe2x80x2,2xe2x80x2,6xe2x80x2-trimethylcyclohexan-1xe2x80x2-yl)pentan-1-en-3-one derivative represented by Formula (1)-1 is subjected to a hydrogenation using a known hydrogenation catalyst described above to obtain a 1-(2xe2x80x2,2xe2x80x2,6xe2x80x2-trimethylcyclohexan-1xe2x80x2-yl)pentan-3-one derivative represented by Formula (1)-3, which is then subjected to a reduction using a known reducing agent described above to obtain a 1-(2xe2x80x2,2xe2x80x2,6xe2x80x2-trimethylcyclohexan-1xe2x80x2-yl)pentan-3-ol derivative represented by Formula (1)-4.
A starting material, Compound (5), can be synthesized by a known citronellal cyclization (JP-A-63-44544) or a methoxycitroneral cyclization (JP-A-4-21642). Alternatively, it can also be available by hydrogenating the double bond of cyclocitral.
A method for synthesizing a compound of Formula (1) of the invention is further detailed below.
An aldol condensation between 2,2,2-trimethylcyclohexane carbaldehyde (5) and a corresponding ketone (R1xe2x80x94CH2xe2x80x94COxe2x80x94CH2xe2x80x94CH2xe2x80x94R2) can be conducted using an ordinary condition as it is.
Abase employed in this reaction may be, for example, an alkaline metal hydride, an alkaline earth metal hydride, an alkaline metal hydroxide or alkoxide, an alkaline earth metal hydroxide or alkoxide oranalkalinemetalamide. Preferably employed are potassium hydride, sodium hydride, lithium hydride, calcium hydride, potassium methoxide, potassium t-butoxide, potassium hydroxide, sodium hydroxide, sodium methoxide, lithium methoxide, calcium hydroxide, barium hydroxide, sodium amide, lithium amide and lithium diisopropylamide. More preferably, potassium hydroxide, potassium methoxide, sodium hydroxide and sodium methoxide are employed.
The amount of a base used ranges from {fraction (1/1000)} to 10 parts by mole based on a ketone as a reaction substrate, preferably {fraction (1/10)} to 5 parts by mole.
The reaction temperature ranges from 0 to 150xc2x0 C., preferably 20 to 100xc2x0 C. The reaction time is preferably 1 to 20 hours. While the amount of a solvent is not particularly limited, it is preferably 0 to 20 parts based on a reaction substrate. Such solvent may be, for example, an alcohol such as methanol and ethanol, an aromatic hydrocarbon such as benzene, toluene and xylene, an aliphatic hydrocarbon such as hexane and heptane, and an ether such as diisopropylether and tetrahydrofuran.
The reduction of a 1-(2xe2x80x2,2xe2x80x2,6xe2x80x2-trimethylcyclohexan-1xe2x80x2-yl)pentan-1-en-3-one derivative represented by Formula (1)-1 or a 1-(2xe2x80x2,2xe2x80x2,6xe2x80x2-trimethylcyclohexan-1xe2x80x2-yl)pentan-3-one derivative represented by Formula (1)-3 can be conducted using an ordinary reducing condition as it is.
A reducing agent may be, for example, a metal hydride such as sodium borohydride and lithium aluminum hydride. The amount of a reducing agent to be used ranges from 1 to 10 parts based on a reaction substrate, preferably 1 to 2 parts. The reaction temperature ranges from xe2x88x9250 to 100xc2x0 C., preferably 0 to 50xc2x0 C. The reaction time is preferably 1 to 20 hours. While the amount of a solvent is not particularly limited, it is 0 to 20 parts based on a reaction substrate, preferably 1 to 10 parts. Such solvent maybe, for example, an alcohol such as methanol and ethanol, an aromatic hydrocarbon such as benzene, toluene and xylene, an aliphatic hydrocarbon such as hexane and heptane, and an ether such as diisopropylether and tetrahydrofuran.
The hydrogenation of a 1-(2xe2x80x2,2xe2x80x2,6xe2x80x2-trimethylcyclohexan-1xe2x80x2-yl)pentan-1-en-3-ol derivative represented by Formula (1)-2 or a 1-(2xe2x80x2,2xe2x80x2,6xe2x80x2-trimethylcyclohexan-1xe2x80x2-yl)pentan-1-en-3-one derivative represented by Formula (1)-1 can be conducted using an ordinary hydrogenation condition as it is.
A hydrogenation catalyst may be, for example, a metal powder itself such as nickel, palladium, rhodium, ruthenium, iridium and platinum, a heterogeneous metal catalyst adsorbed on a support such as a carbon powder, an alumina powder or a silica gel powder, or a homogeneous organic metal catalyst such as a rhodium-phosphine catalyst including a Wilkinson complex or a ruthenium-phosphine catalyst including an ikariya type complex. The amount of a catalyst to be used is 0.01 to 20% by weight based on a reaction substrate, preferably 0.1 to 5% by weight. The reaction temperature is 0 to 200xc2x0 C., preferably20 to 100xc2x0 C. The hydrogen pressure is 1 to200 kg/cm2, preferably 1 to 100 kg/cm2. The reaction time is preferably 1 to 20 hours. While the amount of a solvent is not particularly limited, it is 0 to 20 parts based on a reaction substrate, preferably 1 to 5 parts. Such solvent may be, for example, an alcohol such as methanol and ethanol, an aromatic hydrocarbon such as benzene, toluene and xylene, an aliphatic hydrocarbon such as hexane and heptane, an ether such as diisopropylether and tetrahydrofuran, and an ester such as ethyl acetate and butyl acetate.
Compound (1) of the invention exists as the (R, S) forms with regard to the 1xe2x80x2 position on a cyclohexane ring where a substitution with a side chain occurs and the (R, S) forms with regard to the 6xe2x80x2 position where a substitution with a methyl group occurs, as well as the (R, S) forms with regard to the 3 position when a side chain functionality is an alcohol and the (R, S) forms with regard to the asymmetric carbon atom as a result of a branching of the side chain, thus presenting two or more isomers including optical isomers, and any of the isomers and the mixtures thereof may be employed in the invention.
A melanin production inhibitor of the invention contains as an essential component a trimethylcyclohexane derivative which is Compound (1) of the invention represented by Formula (1): 
wherein A represents Cxe2x95x90O or CHxe2x80x94OH, n represents 2, R1 represents hydrogen or a methyl group, R2 represents a straight or branched, saturated or unsaturated hydrocarbon group having 3 to 10 carbon atoms, and a dotted line represents a saturated or unsaturated carbon-carbon bond. Furthermore, a melanin production inhibitor of the invention may contain as an essential component a trimethylcyclohexane derivative which is Compound (2) represented by Formula (2): 
wherein A represents Cxe2x95x90O or CHxe2x80x94OH, n represents 0, R1 represents hydrogen or a methyl group, R3 represents a straight or branched, saturated or unsaturated hydrocarbon group having 2 to 4 carbon atoms, and a dotted line represents a saturated or unsaturated carbon-carbon bond.
A fragrance fixative of the invention contains as an essential component a trimethylcyclohexane derivative which is Compound (1) of the invention represented by Formula (1): 
wherein A represents Cxe2x95x90O or CHxe2x80x94OH, n represents 2, R1 represents hydrogen or a methyl group, R2 represents a straight or branched, saturated or unsaturated hydrocarbon group having 3 to 10 carbon atoms, and a dotted line represents a saturated or unsaturated carbon-carbon bond.
In addition to such essential component, ketones, aldehydes, esters, alcohols, terpenes, naturally occurring essential oils and other customary fragrances may also be combined in a formulation.
Also by employing a combination of two or more of inventive Compounds (1), the effects of the desirable aroma characteristics and fragrance fixative may further be promoted.
In the invention, a melanin production inhibitor and/or a fragrance fixative may also be contained in a dosage form to give a dermal formulation.
A dermal formulation includes a cosmetic, a pharmaceutical and a designated pharmaceutical, and its dosage form may be selected from those employed usually for a cosmetic, a pharmaceutical and a designated pharmaceutical, such as a lotion, a milky lotion, a facial pack, a foundation, a cream, an ointment, a bath salt, a gel and the like.
While the concentration of a melanin production inhibitor in a dermal dosage form may vary depending on the type of the base employed, other concomitant melanin production inhibitors, if any, and the purpose of the use, it is preferably 0.00001 to 10% by weight based on the total amount of the formulation, more preferably 0.0001 to 5% by weight.
While the concentration of a fragrance fixative in a dermal dosage form may vary depending on the type of the base employed, other concomitant fragrance fixatives, if any, and the purpose of the use, it is preferably 0.00001 to 10% by weight based on the entire amount of the formulation, more preferably 0.0001 to 5% by weight.
A base for a dermal formulation may be any known base for a dermal formulation and is not particularly limited provided that it is inert to a compound of the invention, and may be a solid, a liquid, an emulsion, a foam, a gel and the like.
A dermal formulation of the invention may contain various components employed customarily in a pharmaceutical or a cosmetic such as aqueous components, oily components, powder components, surfactants, humectants, lower or polyhydric alcohols, tackifiers, colorants, flavors, fragrance, antioxidants, pH modifiers, chelating agents, preservatives, UV protecting agents, emulsifiers, anti-inflammatory agents, pharmacologically active components, dermal nutrition supplements and the like, unless the melanin production inhibiting effect, the aroma characteristics and the fragrance fixative of an inventive compound are affected adversely.
In addition to these components, one or more other whitening components maybe incorporated, such as pantetheine-sec-sulfonic acid, isoferulic acid, ascorbic acid and derivatives thereof, arbutin, kojic acid, linolic acid, ellagic acid, glycyrrhetinic acid, a licorice extract and the like, for the purpose of further enhancing the effect.
In addition to these components, one or more other fragrance fixatives may also be incorporated, and dipropylene glycol, benzyl benzoate, trimethyl citrate and diethyl phthalate may be used concomitantly.